tbuckley/cabot-search huggingface dataset:
Miswiring of Merkel cell and pruriceptive C fiber drives the itch-scratch cycle
Authors: Jing Feng, Yonghui Zhao, Zili Xie, Kaikai Zang, Sanja Sviben, Xueming Hu, James A. J. Fitzpatrick, Lu Wen, Yifei Liu, Ting Wang, Katy Lawson, Qin Liu, Yan Yan, Xinzhong Dong, Liang Han, Gregory F. Wu, Brian S. Kim, Hongzhen Hu
Journal: Science Translational Medicine (2022)

Itch sensation provokes the scratch reflex to protect us from harmful stimuli in the skin. Although scratching transiently relieves acute itch through activation of mechanoreceptors, it propagates the vicious itch-scratch cycle in chronic itch by further aggravating itch over time. Although well recognized clinically, the peripheral mechanisms underlying the itch-scratch cycle remain poorly understood. Here, we show that mechanical stimulation of the skin results in activation of the Piezo2 channels on Merkel cells that pathologically promotes spontaneous itch in experimental dry skin. Three-dimensional reconstruction and immunoelectron microscopy revealed structural alteration of MRGPRA3+ pruriceptor nerve endings directed toward Merkel cells in the setting of dry skin. Our results uncover a functional miswiring mechanism under pathologic conditions, resulting in touch receptors triggering the firing of pruriceptors in the skin to drive the itch-scratch cycle.
Targeting KDM4 for treating PAX3-FOXO1–driven alveolar rhabdomyosarcoma
Authors: Shivendra Singh, Ahmed Abu-Zaid, Hongjian Jin, Jie Fang, Qiong Wu, Tingting Wang, Helin Feng, Waise Quarni, Ying Shao, Lily Maxham, Alireza Abdolvahabi, Mi-Kyung Yun, Sivaraja Vaithiyalingam, Haiyan Tan, John Bowling, Victoria Honnell, Brandon Young, Yian Guo, Richa Bajpai, Shondra M. Pruett-Miller, Gerard C. Grosveld, Mark Hatley, Beisi Xu, Yiping Fan, Gang Wu, Eleanor Y. Chen, Taosheng Chen, Peter W. Lewis, Zoran Rankovic, Yimei Li, Andrew J. Murphy, John Easton, Junmin Peng, Xiang Chen, Ruoning Wang, Stephen W. White, Andrew M. Davidoff, Jun Yang
Journal: Science Translational Medicine (2022)

Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3–Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1 + RMS. Genetic and pharmacologic inhibition of KDM4B substantially delayed tumor growth. Suppression of KDM4 proteins inhibited the expression of core oncogenic transcription factors and caused epigenetic alterations of PAX3-FOXO1–governed superenhancers. Combining KDM4 inhibition with cytotoxic chemotherapy led to tumor regression in preclinical PAX3-FOXO1 + RMS subcutaneous xenograft models. In summary, we identified a targetable mechanism required for maintenance of the PAX3-FOXO1–related transcription factor network, which may translate to a therapeutic approach for fusion-positive RMS.
Mepolizumab for chronic rhinosinusitis with nasal polyps (<scp>SYNAPSE</scp>): In‐depth sinus surgery analysis
Authors: Wytske J. Fokkens, Joaquim Mullol, David Kennedy, Carl Philpott, Veronica Seccia, Robert C. Kern, André Coste, Ana R. Sousa, Peter H. Howarth, Victoria S. Benson, Bhabita Mayer, Steve W. Yancey, Robert Chan, Simon B. Gane
Journal: Allergy (2022)

Patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) often require repeat sinus surgery. Mepolizumab reduced the need for sinus surgery in the SYNAPSE trial; this analysis sought to provide a more in-depth assessment of surgery endpoints in SYNAPSE.SYNAPSE was a double-blind Phase III trial (NCT03085797) in adults with recurrent, refractory, severe, CRSwNP eligible for repeat sinus surgery despite standard of care treatments and previous surgery. Patients were randomized (1:1) to mepolizumab 100 mg subcutaneously or placebo, plus standard of care, every 4 weeks for 52 weeks. Time to first inclusion on a waiting list for sinus surgery and time to first actual sinus surgery (both up to week 52) were assessed; the latter endpoint was also analyzed post hoc according to time since last sinus surgery before study screening and baseline blood eosinophil count.Among 407 patients (mepolizumab: 206; placebo: 201), mepolizumab versus placebo reduced the risk of being included on a waiting list for sinus surgery (week 52 Kaplan-Meier probability estimate [95% confidence interval]: 13.9% [9.8%, 19.5%] vs. 28.5% [22.7%, 35.4%]). Mepolizumab versus placebo reduced the risk of sinus surgery irrespective of time (<3 vs ≥3 years) since patients' last sinus surgery prior to study screening (hazard ratios [95% confidence intervals] 0.28 [0.09, 0.84] and 0.50 [0.26, 0.98], respectively) and baseline blood eosinophil count.Mepolizumab reduced the risk of further sinus surgery in patients with recurrent, refractory, severe CRSwNP, irrespective of the patient baseline characteristics assessed.
Association Between Time to Source Control in Sepsis and 90-Day Mortality
Authors: Katherine M. Reitz, Jason Kennedy, Shimena R. Li, Robert Handzel, Daniel A. Tonetti, Matthew D. Neal, Brian S. Zuckerbraun, Daniel E. Hall, Jason L. Sperry, Derek C. Angus, Edith Tzeng, Christopher W. Seymour
Journal: JAMA Surgery (2022)

Rapid source control is recommended to improve patient outcomes in sepsis. Yet there are few data to guide how rapidly source control is required.To determine the association between time to source control and patient outcomes in community-acquired sepsis.Multihospital integrated health care system cohort study of hospitalized adults (January 1, 2013, to December 31, 2017) with community-acquired sepsis as defined by Sepsis-3 who underwent source control procedures. Follow-up continued through January 1, 2019, and data analyses were completed March 17, 2022.Early (<6 hours) compared with late (6-36 hours) source control as well as each hour of source control delay (1-36 hours) from sepsis onset.Multivariable models were clustered at the level of hospital with adjustment for patient factors, sepsis severity, resource availability, and the physiologic stress of procedures generating adjusted odds ratios (aOR) and 95% CI.Of 4962 patients with sepsis (mean [SD] age, 62 [16] years; 52% male; 85% White; mean [SD] Sequential Organ Failure Assessment score, 3.8 [2.5]), source control occurred at a median (IQR) of 15.4 hours (5.5-21.7) after sepsis onset, with 1315 patients (27%) undergoing source control within 6 hours. The crude 90-day mortality was similar for early and late source control (n = 177 [14%] vs n = 529 [15%]; P = .35). In multivariable models, early source control was associated with decreased risk-adjusted odds of 90-day mortality (aOR, 0.71; 95% CI, 0.63-0.80). This association was greater among gastrointestinal and abdominal (aOR, 0.56; 95% CI, 0.43-0.80) and soft tissue interventions (aOR, 0.72; 95% CI, 0.55-0.95) compared with orthopedic and cranial interventions (aOR, 1.33; 95% CI, 0.96-1.83; P < .001 for interaction).Source control within 6 hours of community-acquired sepsis onset was associated with a reduced risk-adjusted odds of 90-day mortality. Prioritizing the rapid identification of septic foci and initiation of source control interventions can reduce the number of avoidable deaths among patients with sepsis.
Health policy priorities for the next prime minister
Authors: Hugh Alderwick
Journal: BMJ (2022)

Health policy priorities for the next prime ministerAvoid zombie policies and invest in growing the workforce and reducing inequalities Hugh Alderwick director of policyThe UK will soon have a new prime minister.Boris Johnson stepped down as Conservative party leader on 7 July 2022, after a week of mass government resignations removed his already diminished political authority.Johnson intends to stay on
A unique skin phenotype resulting from a large heterozygous deletion spanning six keratin genes
Authors: Janan Mohamad, Ofer Sarig, Paula Beattie, Kiril Malovitski, Sari Assaf, Edel O’Toole, Janice Schwartz, Holly Evans, Liat Samuelov, Eli Sprecher
Journal: British Journal of Dermatology (2022)

The phenotypic spectrum of genodermatoses is continuously expanding. Three siblings were referred because of a highly unusual phenotype comprising alopecia, dystrophic nails, palmoplantar keratoderma and trauma-induced skin blistering. Whole-exome sequencing analysis identified a heterozygous large genomic alteration of around 116 0000 bp resulting in the deletion of the KRT9, KRT14, KRT15, KRT16 and KRT19 genes, as well as part of KRT17. This genomic change leads to the generation of a truncated keratin 17 (KRT17) protein encoded by the first three exons of the gene and part of intron 3. The three patients were found to carry the heterozygous genomic deletion while their healthy parents did not, indicative of germline mosaicism. The genomic alteration was found to result in reduced KRT17 expression in patient skin. More importantly, the abnormal truncated KRT17 was found to exert a deleterious effect on keratinocyte cytoskeleton formation, leading to keratin aggregation. Coexpression of wildtype and truncated KRT17 proteins also caused keratin aggregation, demonstrating that the deletion exerts a dominant negative effect. In conclusion, we are reporting on a novel clinical phenotype that was found to result from germline mosaicism for a large genomic deletion spanning six keratin genes, thus expanding the spectrum of clinical manifestations associated with keratin disorders. What is already known about this topic? Various conditions known as keratinopathies have been shown over recent years to be associated with dominant or recessive variants in several individual keratin genes. What does this study add? We report three patients presenting with a unique clinical phenotype that was found to result from germline mosaicism for a large genomic deletion spanning six keratin genes. The genomic variant is predicted to result in a truncated form of keratin 17, which was found in an in vitro assay to disrupt keratinocyte cell cytoskeleton formation.
Pronouncing my name as best you can matters to me as your colleague
Authors: Su Ling Yeoh
Journal: BMJ (2022)

Ovarian cancer accounts for more deaths than any other cancer of the female reproductive system. Patients bearing ovarian tumors infiltrated with high frequencies of T cells associate with a greater survival probability. However, therapeutic strategies targeting T cells in ovarian cancers are largely ineffective. We have observed in our models of late-stage murine ovarian cancer that in the absence of Toll-Like Receptor 5 (TLR5) signaling, anti-PD-L1 therapy promotes significant survival and subsequent protection against tumor rechallenge. Ovarian tumors from rechallenged TLR5KO mice exhibited significantly higher frequency/number of both CD4 and CD8 effector memory T cell subsets and greater numbers of antigen experienced T cells. Thus, in the absence of TLR5 signaling, T cells are better able to mount/maintain a response to ovarian tumors after inhibitory receptor blockade. Furthermore, protection against tumor progression in TLR5KO mice corresponds with a significant increase in tumor infiltrating cross presenting and IL-12 producing Dendritic cells (DCs) which could account for the differences in T cell infiltrates. We hypothesize that TLR5 signaling functionally alters DCs to become more suppressive in the tumor microenvironment, impacting T cell differentiation and anti-tumor activity, thereby reducing survival during ovarian tumor progression with aPD-L1 therapy. Clinical implications are already present, as roughly 7.5% of the general population harbor a TLR5 SNP that diminishes TLR5 signaling and is associated with increased long-term survival for ovarian cancer patients. Therefore, patients who express the TLR5 SNP may immediately benefit from anti-PDL1 therapy and those without the SNP, TLR5 antagonism. Supported by NIH/NCI 1R01CA253285 UVA CIC Collaborative Grant
Randomized Phase IIa Clinical Study of an Anti-α<sub>v</sub>β<sub>6</sub>Monoclonal Antibody in Idiopathic Pulmonary Fibrosis
Authors: Ganesh Raghu, Majd Mouded, Antje Prasse, Christopher Stebbins, Guolin Zhao, Guochen Song, Million Arefayene, Shelia M. Violette, Diana Gallagher, Kevin F. Gibson
Journal: American Journal of Respiratory and Critical Care Medicine (2022)
Improved Computed Tomography Performance in Blunt Abdominal Trauma—Has Our Care Kept Pace?
Authors: Tanya N. Rinderknecht, Edgardo S. Salcedo, James W. Holcroft
Journal: JAMA Surgery (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Evaluation of Adherence to Venous Thromboembolism Prophylaxis Guidelines Among US Adults After Pancreatic Cancer Surgery
Authors: Lauren M. Perry, Sarah B. Bateni, Ryan P. Merkow, Robert J. Canter, Richard J. Bold, Julie Hallet, Sepideh Gholami
Journal: JAMA Surgery (2022)

This cohort study evaluates postoperative adherence to venous thromboembolism prophylaxis guidelines among US adults with pancreatic cancer using a national population sample drawn from Surveillance, Epidemiology, and End Results–Medicare data.
A prospective national cohort evaluating ring MVA vaccination as post-exposure prophylaxis for monkeypox
Authors: Liem Binh Luong Nguyen, Jade Ghosn, Christine Durier, Carla Tachot, Eric Tartour, Amel Touati, Tabassome Simon, Brigitte Autran, Inmaculata Ortega Perez, Erica Telford, Jeremy K Ward, David Michels, Laurence Meyer, Alexandra Rousseau, Laurence Berard, Xavier de Lamballerie, Odile Launay
Journal: Nature Medicine (2022)
Transdisciplinary Science and Research Training in Psychiatry
Authors: Charles F. Reynolds, Myrna M. Weissman
Journal: JAMA Psychiatry (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
Validation of the new 2021 EASL algorithm for the noninvasive diagnosis of advanced fibrosis in NAFLD
Authors: Clémence M. Canivet, Charlotte Costentin, Katharina M. Irvine, Adèle Delamarre, Adrien Lannes, Nathalie Sturm, Frederic Oberti, Preya J. Patel, Thomas Decaens, Marie Irles‐Depé, Isabelle Fouchard, Paul Hermabessière, Marine Roux, Justine Barthelon, Paul Calès, Elizabeth E. Powell, Victor de Ledinghen, Jérôme Boursier
Journal: Hepatology (2022)

Background and Aims: The European Association for the Study of the Liver (EASL) has recently proposed an algorithm for the diagnosis of advanced liver fibrosis. We aimed to evaluate the diagnostic accuracy of this algorithm in nonalcoholic fatty liver disease (NAFLD). Approach and Results: One thousand fifty‐one patients with NAFLD, liver biopsy, and four noninvasive tests (NITs; Fibrosis‐4 [FIB4], vibration controlled transient elastography [VCTE], FibroMeter, Fibrotest) were included. The enhanced liver fibrosis (ELF) score was available in 396 patients. A cohort of 230 patients from primary care/diabetes clinics had FIB4, VCTE, and ELF. Compared with the performance of single NITs, agreement between two NITs (FIB4 and VCTE, VCTE and patented serum tests) increased specificity and positive predictive value by 20%, thus justifying the sequential use proposed in the EASL algorithm. The FIB4/VCTE/FibroMeter and FIB4/VCTE/Fibrotest algorithms performed similarly, providing 85% diagnostic accuracy and a liver biopsy requirement rate of only 10%. The FIB4/VCTE/ELF algorithm performed similarly in the subgroup where ELF was available. Simulations of algorithm accuracies at different prevalence showed that positive predictive values rapidly increased, reaching a plateau above 75% starting at 15% prevalence. Negative predictive values remained higher than 90% up to 25% prevalence. The rate of liver biopsy requirement remained stable, increasing by only 5% between low and high prevalence settings. When the EASL algorithm was applied in the primary care/diabetes clinic cohort, liver biopsy requirement was only 3%, and the agreement among the three steps provided 75% positive predictive value. Conclusions: Our study validates the algorithm proposed by the EASL in its latest 2021 guidelines for the diagnosis of advanced fibrosis in the setting of NAFLD.
Skeletonized Internal Thoracic Artery—Post Hoc Analysis vs Clinical Practice
Authors: Gabriele M. Iacona, Abeel A. Mangi
Journal: JAMA Cardiology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
NK cells with tissue-resident traits shape response to immunotherapy by inducing adaptive antitumor immunity
Authors: Nicole Kirchhammer, Marcel P. Trefny, Marina Natoli, Dominik Brücher, Sheena N. Smith, Franziska Werner, Victoria Koch, David Schreiner, Ewelina Bartoszek, Mélanie Buchi, Markus Schmid, Daniel Breu, K. Patricia Hartmann, Polina Zaytseva, Daniela S. Thommen, Heinz Läubli, Jan P. Böttcher, Michal A. Stanczak, Abhishek S. Kashyap, Andreas Plückthun, Alfred Zippelius
Journal: Science Translational Medicine (2022)

T cell–directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen the clinical benefit of immunotherapies. Here, we demonstrate that therapeutic targeting of the interferon-γ (IFN-γ)–interleukin-12 (IL-12) pathway relies on the ability of a population of natural killer (NK) cells with tissue-resident traits to orchestrate an antitumor microenvironment. In particular, we used an engineered adenoviral platform as a tool for intratumoral IL-12 immunotherapy (AdV5–IL-12) to generate adaptive antitumor immunity. Mechanistically, we demonstrate that AdV5–IL-12 is capable of inducing the expression of CC-chemokine ligand 5 (CCL5) in CD49a + NK cells both in tumor mouse models and tumor specimens from patients with cancer. AdV5–IL-12 imposed CCL5-induced type I conventional dendritic cell (cDC1) infiltration and thus increased DC-CD8 T cell interactions. A similar observation was made for other IFN-γ–inducing therapies such as Programmed cell death 1 (PD-1) blockade. Conversely, failure to respond to IL-12 and PD-1 blockade in tumor models with low CD49a + CXCR6 + NK cell infiltration could be overcome by intratumoral delivery of CCL5. Thus, therapeutic efficacy depends on the abundance of NK cells with tissue-resident traits and, specifically, their capacity to produce the DC chemoattractant CCL5. Our findings reveal a barrier for T cell–focused therapies and offer mechanistic insights into how T cell–NK cell–DC cross-talk can be enhanced to promote antitumor immunity and overcome resistance.